9-Amino-3-(amino or nitro)-1,5-dioxaspiro{8 5.5{9 undecane derivatives

ABSTRACT

9-(Ac1NH)-3-Q-3-R-9-R&#39;&#39;-1,5-dioxaspiro(5.5)undecane (I), where R and R&#39;&#39; are each hydrogen or lower-alkyl, Ac1 is hydrogen or lower-alkanoyl and Q is NO2 or NH2, are useful intermediates for the preparation of antifertility agents, namely, 3-(Ac4NH)-9(Ac3NH)-3-R-9-R&#39;&#39;-1,5-dioxaspiro(5.5)undecane (II), where Ac3 is lower-alkanoyl or 4-Q1-benzoyl, Ac is 4-Q2-benzoyl, Q1 and Q2 are each lower-alkoxy or polyhalo-lower-alkoxy, and, R and R&#39;&#39; are each hydrogen or lower-alkyl. II is prepared by diacylating I where Ac1 is hydrogen and Q is NH2 (VII) or by monoacylating I where Ac1 is lower-alkanoyl and Q is NH2 (VI). VI and VII are prepared stepwise as follows: 4-(Ac5NH)-4-R&#39;&#39;-cyclohexanol (X), where Ac5 is lower-alkanoyl, is oxidized to produce 4-(Ac5NH)-4R&#39;&#39;-cyclohexanone (III); III is reacted with 2-NO2-R-1,3propanediol (IV) to produce 9-(Ac5NH)-3-nitro-3-R-9-R&#39;&#39;-1,5dioxaspiro(5.5)undecane (V); V is reduced to produce 3-amino-9(Ac5NH)-3-R-9-R&#39;&#39;-1,5-dioxaspiro(5.5)undecane (VI); and, VI is hydrolyzed to produce 3-R-9-R&#39;&#39;-1,5-dioxaspiro(5.5)undecan-3,9diamine (VII). Methods of preparing X are given. Bis(polyhaloacetyl) derivatives of VII are prepared.

United States Patent [1 1 Gelotte et al.

[ 9-AMINO-3-(AMINO OR NITRO)-l,5-DIOXASPIRO[ 5.5 ]UNDECANE DERIVATIVES[52] US. Cl 260/340.7; 424/278 [51] Int. Cl. C07D 319/06; A61K 31/335[58] Field of Search 260/340.7

[56] References Cited UNITED STATES PATENTS 6/l94l Senkus ..260/340.71/1945 Senkus ..260/340.7

QTI-IER PUBLICATIONS Wagner et al., Synthetic Orgame Chemistry, J. Wiley& Sons, Inc., New York, (1953), pp. 6789.

Primary Examinen-Anton I-I. Sutto Attorney, Agent, or Firm-Robert K.Bair; B. Woodrow Wyatt July 15,1975

[57] ABSTRACT ane (I), where R and R are each hydrogen or IOW6I'r alkyl,Ac, is hydrogen or lower-alkanoyl and Q is NO. or NH;, are usefulintermediates for the preparation of antifertility agents, namely, 3-(AcNI-I)-9-(Ac NH)-3- R-9-R'-1,5-dioxaspiro[5.5]undecane (II), where Ac islower-alkanoyl or 4-Q,-benzoyl, Ac is 4-Q -benzoyl, Q and Q, are eachlower-alkoxy or polyhalo-loweralkoxy, and, R and R are each hydrogen orloweralkyl. II is prepared by diacylating I where Ac, is hydrogen and Qis NI-I (VII) or by monoacylating I where Ac, is lower-alkanoyl and Q isNI-I (VI). VI and VII are prepared stepwise as follows: 4-(Ac ,NI-I)-4-R-cyclohexanol (X), where Ac is lower-alkanoyl, is oxidized to produce4-(Ac Nl-I)-4R- cyclohexanone (III); III is reacted with 2-NO -R-1,3-propanediol (IV) to produce 9-(Ac NI-I)-3-nitro-3-R-9-R'-1,5-dioxaspiro[5.5]undecane (V); V is reduced to produce3-amino-9-(Ac NH)-3-R-9-R-I,5-dioxaspiro[5.5]undecane (VI); and, VI ishydrolyzed to produce 3-R-9-R'rl,5-dioxaspiro[5.5]undecan-3,9- diarnine(VII). Methods of preparing X are given. Bis(polyhaloacetyl) derivativesof VII are prepared,

10 Claims, No Drawings 1 9-AMINO-3-(AMINO onNITRO)-1,5-DIOXASPIRO[5,5]UNDECANE DERlVATIVES COMPOSITIONS AND THEIRPREPARATION This invention relates to compositions of matter known inthe art of chemistry as l,5-dioxaspiro[ 5.5 ]undecanes and to theirpreparation.

The invention in its composition aspect resides in the compoundsrepresented by the formula I 3 I Ac NH 3 Q where R and R are eachhydrogen or lower-alkyl, Ac, is hydrogen, lower-alkanoyl orpolyhaloacetyl only when Q is NHAc and, Q is N NI-I or NI-IAc where Ac,is polyhaloacetyl. The compounds of formula I where Ac, is hydrogen orlower-alkanoyl and Q is N0 or NH are useful as intermediates in thepreparation of compounds of the formula II NH HA6 )4 where R and R areeach hydrogen or lower-alkyl, AC3 is lower-alkanoyl or 4-Q,-benzoyl, andAc, is'4-Q benzoyl, where Q, and Q each is lower-alkoxy orpolyhalo-lower-alkoxy. The compounds offormula I where Ac, ispolyhaloacetyl and Q is NHAc i.e., polyhaloacetamido, are useful ascharacterizing derivatives of the intermediate diamines of formula Iwhere Ac, is hydrogen and Q is NI-I I The compounds of formula II andtheir preparation either by diacylation of the diamine of formula'l,i.e., where Ac, is hydrogen and Q is NH or by monoacylation of themonamine of formula I, i.e., where Ac, is lower-alkanoyl (also where Ac,is 4-Q,-benzoyl as defined above) andQ is NH are disclosed and claimedin copending-US. Pat. application Ser. No. 462,388, filed Apr. 19, 1974.The compounds of formula II are useful as antifertility agents. 7

Preferred embodiments of the instant invention are the compounds offormula I where R is hydrogen and R is lower-alkyl; particularlypreferred embodiments of this aspect of the invention are the compoundsof for mula I where R is hydrogen, R is methyl or ethyl, Ac, is hydrogenor acetyl and Q is NH Lower-alkyl, as used herein, e.g., as one of themeanings for R or R in formulas I 012'" hereinabove or as one of themeanings for R orR' in formulas III, V,

III 1 VI or VII hereinbelow, is an alkyl radical, preferably having fromone tofour carbon atoms, which can be arranged as straight or branchedchains including, for instance, but without limiting the generality ofthe foregoing, methyl, ethyl, n-propyl, isopropyl, n-butyl, secbutyl,isobutyl and tert-butyl.

Lower-alkanoyl, as used herein, e.g., as one of the meanings for Ac, informula I, as one of the meanings for AC3 in formula II or as themeaning for A0,, in formulas III, V and VI, is an alkanoyl radicalpreferably having from two to four carbon atoms, illustrated by ethanoyl(acetyl), propanoyl (propionyl), n-butanoyl (butyryl),2-methylpropanoyl, and the like.

Polyhaloacetyl, as used herein, e.g., as one of the meanings for Ac, oras the meaning for Ac in the definitions of the terms of formula Ihereinabove, is dihaloacetyl or trihaloacetyl where halo is fluoro.chloro, bromo or iodo, illustrated by difluoroacetyl, dichloroacetyl,dibromoacetyl, diiodoacetyl, trifluoroacetyl, trichloroacetyl,tribromoacetyl and triiodoacetyl. I

Lower-alkoxy, as used herein, e.g., as one of the meanings for Q, and Oin the definitions of the terms of formula II hereinabove, is an alkoxyradical, preferably having'from one to four carbon atoms, which can bearranged as straight or branched'chains, including, for instance, butwithout limiting'the generality of the foregoing, methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert-butoxy.

v Polyhalo-lower-alkoity, as used herein, e.g., as one of the meaningsfor Q, and O in the definitions of formula II hereinabove, is an alkoxyradical, preferably having from one to four carbon atoms and having fromtwo to five halo' substituents, i.e., fluoro, chloro, bromo and iodo,preferably fl uo ro and chloro, illustrated by dichloromethyl,difluoromethyl, dibromomethyl,-diio- 'domethyl, trichloromethyl,trifluoromethyl, 2-chloro- 1,1,2-trifluoroethyl, 2,2,2-trichloroethyl,2,2,2- trifluoroethyl, l, I ,2,2,2'-pentafluoroethyl, l, l2,2-tetrafluoro-n-butyl, 2,2,3,3,3-pentafluoropropyl, and the like.

The invention in a process aspect comprises the steps of reacting4 (AcNH)-4-R-cyclohexanone (III) with 2-R-2-nitro-I,3-propanediol (IV)' toproduce 3-nitro-3- reducing V toproduce 3 aminO-3-R-9-(AC NI-II-Q-Rl,5-dioxaspiro[5.5]undecane (VI) and hydrolyzing VI to produce3-R-9-R-l,5-dioxaspiro[5.5]undecan-3,9- diamine (VII), wherein AC5 islower-alkanoyl, and R and R are each hydrogen or lower-alkyl. Inaddition't'o the 'above combination of three steps, other processaspects of the invention are each individual step and the twoconsecutive combinations of two steps. The foregoing steps of theprocess aspects of the invention are illustrated structurally asfollows:

X HO'CH 2 Ac NH 0 N 5 2 IV 1 v R RI l R 03F I m HN 0 2 AC5, NH

-cyclohexanol (VIII) where R is lower-alkyl is-conve- 3 One method ofpreparing the starting 4-(Ac' N-H) 4- R-cyclohexanone (III) Comprisesthetwo steps illustrated structurallyas follows: l

EO-ozr Ac -halide Ha I v I A95 VIII IX RI i x .L l Y Y Ac NH I :1 Thus,in the first step the 4-amino-4-R-cyclohexanol (VIII) is reacted withone molar equivalentiof alqweralkanoylating agent, preferably with alower-alkanoyl halide (IX), preferably chloride, to produce 4-(Ac NH)-4-R-cyclohexanol (X) which in the,second' step is oxidized, e.g., withchromium trioxide, vto-produce the corresponding 4-.(Ac NH)y4-R-cyclohexanone (Ill) where Ac ,,R' and R have the meanings givenhereinabove. Alternatively,,;. the 4-(Ac NH)-4-R'-cyclohexanol (X) whereR is hydrogen is readily. prepared by catalytic-hydrogenationof thecorresponding 4-(Ac NI-l)phenol (,X I-), as illustrated hereinbelowinthe specific exemplary disclosure. The initial starting materials(VIl-Iand XI); ,are known or are readily prepared from known compounds usinggenerally known procedures which areillustrated hereinbelow. Similarly,other reactants used inthe foregoing reaction sequences, e.g., IV, areknown-or areprepared: readilyfrom known compounds. using generally knownprocedures.

Preparation of the starting- 4-amino- 4,-R'-

niently carried out by the nucleophilic addition of;a,lower-alkanenitrile, preferably acetonitrile, to 4-R'-3- cyclohexenolin the presence of a strong acid and hydrolyzing the resulting3,5-di-(lower-alkyl)-2-oxa-4- azabicyclo[3.2.21-3-nonene in the form ofits ,acidaddition salt, e.g., bisulfate if sulfuric acid is-used as thestrong acid. The intermediate 4-R 3-cyclohexenolsare generally known andare prepared stepwise the known procedure of first reducing 4-R';anisolewith lithium and liquid ammonia in ether to produce 4:-R.'.- .I-

methoxy-l,4-cyclohexadiene or methyl enol ether, of 4-R-3-cyclohexenone,next reacting said enol vether with a strong acid, e.g., aqueous oxalicacid, to produce 4-R'-3-cyclohexe'none and reducing the latter withlit-hium aluminum hydride in ether, to produce 4 -R -'3- cyclohexenol.

Disclosed and claimed in said copend ing US. Pat.

application Ser. No. 462,388 is the p'rocess for preparing the compoundsof formula II where Ac p is the same as Ac, which comprises reacting3-R-9-R'-l,5"-"

dioxaspiro[5.5]undecan-3,9-diamine of the formulatir.

VII

R' O R VII the formula XJII.

.4 for formula I, with a*4=Qg-benzoylating agent, preferablywith.atgleast:itwdsmolar Equivalents of a 4-02- benzoyl halide offormula xllu '2 where 0 is defined above i n the definition of formulaII. 4 g I Also disclosed and claimed in copending US. Pat.

application Ser. Np' 462,388 is the process for preparing the compoundsof formula II where Ac; and Ac, are different which comprises reactingan N-( 3-amino-3-R- where R, .R and A0 have the meanings given above forformula ll,, with a l-Qfbenaoylating agent, preferably with, atleast onemolar equivalent of, a 4-Q -benzoyl halide of formula XII, as: givenabove. i i

he, nature of the starting materials, mo

{ sis, results of elementary analyses} examination v,of

gether, confirm the moleculargstructure: assigned to The manner andprocess; riiaking and using thei n- ,vention will now,be,. g enerallydescribed so as to enable apersoii ski lledy iri the a r tpof medicinalchemistry to make and use the'same, as follows; i

at about 50l50C., preferably about 90C. and preferably in the presenceof an acid catalyst and ft preferably removing from the reaction mixturethe wateiflforrned by the reaction. The reaction medium is preferably awater-immiscible, non-polar solvent inert to the reaction conditions,e.g., benzene, toluene, xylene, chloroform, carbon tetrachloride, andthe like. The reaction is run preferably in refluxing benzene inthegpresence of p-toluenesulfonic acid as an acid catalyst andpreferably having a continuous separator connected to the reactionvessel to collect the water formed by the reaction. The acid as catalystcan be any strong acid in catalytic amount, including strong inorganicacids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, and the like, and organic sulfonic acids, e.g.,p-toluenesulfonic, benzenesulfonic acid, methanesulfonic acid,ethanesulfonic acid, and the like. The reaction also can be run using amolar equivalent quantity of boron trifluoride etherate which acts bothan acid catalyst and an agent capable of removing the water formed bythe reaction.

The reaction of reducing 3-nitro-3-R-9-(Ac NH)-9-R-l,5-dioxaspiro[5.5]undecane (V) to produce 3- amino-3-R-9-(AcNI-I)-9-R'-1,5-dioxaspiro[5.5]undecane (VI) is carried out by reactingVwith a reducing agent effective to reduce nitro to amino. The reductionnis preferably run by catalytic hydrogenation in a solvent inert underthe reaction conditions, e.g., ethanol, dimethylformamide,tetrahydrofuran, and the like, in the presence of a suitablehydrogenation catalyst, e.g., Raney nickel, platinum oxide,palladium-oncharcoal, other noble metal catalysts, and the like.

The hydrolysis of 3-amino-3-R-9-(Ac Nl-I)-9-R'-l,5-dioxaspiro[5.5]undecane (VI) to produce 3-R-9-R'-I,5-dioxaspiro[5.5]undecan-3,9-diamine (VII) is readily carried out byheating VI at about 50l50C., preferably about 90-l 10C., in aqueousalkali hydroxide solution, preferably aqueous sodium or potassiumhydroxide solution. The hydrolysis also can be run using an alkalialkoxide in a lower-alkanol, e.g., sodium or potassium methoxide inmethanol, sodium or potassium ethoxide in ethanol, sodium or potassiumisobutoxide in isobutyl alcohol.

The reaction of 4-amino-4-R-cyclohexanol (VIII) with one molarequivalent of a lower-alkanoylating agent to produce 4-(AcNH)-4-R-cyclohexanol (X) is preferably carried out by reacting VIII witha loweralkanoyl halide (IX) at about -5 to. 10C. in the presence of anacid-acceptor, e.g., an alkali carbonate or bicarbonate or hydroxide, bystirring VIII and IX in a reaction medium comprising water and asuitable water-immiscible organic solvent inert under the reactionconditions, e.g., ethylene dichloride, methylene dichloride, ether,benzene, and the like. Alternatively, other lower-alkanoylating agents,e.g., lower-alkanoic acid anhydride and lower-alkyl lower-alkanoate, canbe used and non-aqueous media can be used, e.g., pyridine or otheracid-acceptor solvents are conveniently used with a lower-alkanoylhalide, e.g., acetyl chloride, as the loweralkanoylating agent; in fact,an non-aqueous medium such as pyridine is preferred when the highlyreactive acetyl chloride is used. Another convenient method of preparing4-(Ac NH)-4-R'-cyclohexanol (X) where R is hydrogen comprises thecatalytic hydrogenation of the corresponding 4-(Ac NH)phenol (XI), asillustrated hereinbelow.

Preparation of the 4-amino-4-R'-cyclohexanol (X) where R is lower-alkylis carried out by carefully mixing 4-R'-cycIohex-3-enone with a chilledmixture of the alkanenitrile and strong acid, preferably concentratedsulfuric acid, preferably keeping the temperature of the reactionmixture between about l0C. and +l0C. The reaction mixture, whichcontains 3,5-di-(loweralkyl)-2oxa-4-azabicyclo[3.2.2]-3 nonene in theform of its acid-addition salt, e.g., bisulfate when sulfuric acid isused as the strong acid, is then allowed to warm up to room temperature.Hydrolysis of the said 2-oxa- 4-azabicyclo[3.2.2]-3-nonene is achievedby adding water to the reaction mixture and heating it at about75-l25C., preferably between 90l10C., conveniently done on a steam bath.

The oxidation of 4-(Ac NH)-4-R-cyclohexanol (X) to yield 4-(AcNI-I)-4-R'-cyclohexanone (III) is generally carried out by reacting Xwith an oxidizing agent capable of converting secondary alcohols toketones. Preferred oxidizing agents are chromium trioxide in acetic orsulfuric acids or in pyridine, sodium or potassium dichromate andsulfuric acid, and the like. In preparaing these intermediates (III)stoichrometric quantities of chromium trioxide in aqueous sulfuric acidis used first mixing the reactants carefully while maintaining thereaction temperature at about 15C. and then allowing for completion ofthe reaction at room temperature, i.e., about 25C.

The compounds of formula II where AC3 is the same as Ac, are preferablyprepared by reacting the appropriate diamine of formula VII with atleast two molar equivalents of the 4-Q -benzoyl halide of formula XII inthe presence of an acid-acceptor, that is, a basic substance capable ofneutralizing the hydrogen halide formed by the reaction, for example, analkali carbonate, preferably sodium carbonate or potassium carbonate, analkali hydroxide, preferably sodium hydroxide or potassium hydroxide.The reaction was carried out preferably by carefully mixing thereactants with cooling (to about 0 to 10C.) and stirring in a mediumcomprising water and a suitable water-immiscible organic solvent inertunder the reaction conditions, e.g., ethylene dichloride, chloroform,methylene dichloride, benzene, ether, and the like; the reaction mixturepreferably was then allowed to warm up to room temperature and to standwith stirring until the reaction was completed.

The compounds of formula II where Ac and Ac are different are preparedby reacting an N-(3-amino-3-R-19-R'-l,5-dioxaspiro[5.5]undecan-9-yl)-acylamide of formula XIII with amolar equivalent of the 4-Q benzoyl halide of formula XII using theabovedescribed reaction conditions used for preparing the compounds offormula I where Ac is the same as Ac Alternatively, other available 4-Q-benzoylating agents can be used in place of said 4-Q -benzoyl halidesin the above-noted processes of preparing the compounds of formula IIwhere AC3 is the same as and where it is different from Ac,,: Forexample, these 4-Q benzoylations can be carried out by heating aloweralkyl 4-Q -benzoate with a diamine of formula VII or a monamine offormula XIII or VI or by reacting 4-Q benzoic anhydride with saiddiamine or monamine. Also the products of formula II are obtained byheating said diamine or monamine with a 4-Q -benzoic acid either in theabsence or presence of a suitable solvent, for example,dimethylformamide, tetrahydrofuran, benzene, ethylene dichloride, andthe like, and either in the absence or presence of a dehydrating or anactivating agent, e.g., dicyclohexylcarbodiimide, l lcarbonyldiimidazole and the like.

The best mode contemplated for carrying out the invention will now beset forth as follows.

A. 4-ALKANOYLAMINOCYCLOI-IEXANOLS l. 4-Acetamidocyclohexanol A solutionof 64.0 g. of 4-acetamidophenol in 400 ml. of ethanol also containing1.0 g. of 5% rhodium-on-alumina was hydrogenated at 95-l33C. for fourhours at a starting hydrogen pressure of 1850 psi. Since only 34% of thetheoretical quantity of hydrogen had been taken up, an

additional 3.0 g. of 5% rhodium-on-alumina was added 7 filtered off andthe solvent was distilled off in vacuo to yield, as a white solid, 70.5g. of 4- acetamidocyclohexanol. A small portion-of this compound meltedat 160162.5C. after recrystallization from acetone. i

2. 4-AcetamidoA-methylcyclohexanol A mixture containing 12.9 g. of4-amino-4-methylcyclohexanol, 10.2 g. of acetic anhydride, 1.7 g. ofsodium, acetate and ml. of glacial acetic acid is refluxed with stirringfor 90 minutes, cooled to room temperature, 10 ml. of water added andchilled. The resulting precipitate is collected, washed with cold waterand dried in vacuo at 60C. to yield 4-acetamido-4-methylcyclohexanol.

The above intermediate 4-amino-4- methylcyclohexanol was prepared asfollows: To ml. of chilled concentrated sulfuric acid was added dropwisewith stirring 20 ml. of acetonitrile at such a rate to maintain thetemperature between 5 and +5C. To the resulting solution kept below 10C.was added dropwise with stirring over a period of about minutes asolution containing 11.3 g. of 4-methyl-3- cyclohexenol in 10 ml. ofacetonitrile. The clear brown solution was allowed to stand at 5C. overthe weekend (about hours) and then poured onto 500 g. of ice. Theresulting solution, which contains 3,5-dimethyl-2-oxa-4-azabicyclo[3.2.2]-3-nonene as its bisulfate acidaddition salt, wasstirred on a steam bath for 7 hours; the hot mixture was treated withdecolorizing charcoal and filtered; and, the resulting filtrate wastreated with a solution of 50 g. of sodium hydroxide in ml. of water.The resulting solution was concentrated in vacuo to one-half volume,made strongly basic with 35% aqueous sodium hydroxide solution and thealkanine solution extracted, with methylene dichloride (4 X 75 .ml.).The combined extracts were dried over anhydrous potassium carbonate andthe solvent distilled off in vacuo to yield, as a clear, very viscuousoil, 6.25 g. of 4-amin0-4-methylcyclohexanol.

Following the procedure described in the immediately preceding paragraphbut using a molar equivalent quantity of 4-ethyl-3-cyclohexenol in placeof 4-methyl-3-cyc1ohexenol, there is obtained 4-amino-4-ethylcyclohexanol.

lnv the-foregoing preparations of 4-amino-4-(lower alkyl)-cyclohexanolsthe intermediate 3,5-di-(loweralkyl-)2-oxa-4-azabicyclo[3.2.2]-3-n.onane and, acidaddition salt can beisolated before conversion by.hydrolysis to said4-amino-4-(lower-alkyl)-cyclohexano1, as illustrated as follows: To astirred and chilled (to 20C. using a solid carbon dioxide-isopropylalcohol bath) of ml. of concentrated sulfuric acid was added dropwise 40ml of acetonitrile at sucha rate that the reaction temperature'did notexceed +5C. To the resulting chilled solution was added dropwise withstirring and cooling a solution of 27.4 g. of 4-methyl-3- cyclohexenolin 20 ml. of acetonitrile, keeping the reaction temperature below +5C.The resulting reaction solution was kept at 0C. for 45 minutes and thenallowed to warm up to room temperature (about 25C.) and stand for aboutsixteen hours (overnight). The reaction solution was slowly poured intoa solution of g. of sodium hydroxide in 600 -ml. of ice waterovfi i aperiod of 60 minutes. The precipitated sodium sulfate was filtered offand the filtrate was extracted with .chloroform (5 X 75 ml.). Theextract was dried over anhydrous magnesium sulfate, the solvent removedby disti1- lation under reduced pressure and the residualoilifractionally distilled under reduced pressure-to yield, as a clearcolorless oil, 17.5 g. of -3,5-dimethyl-2-oxa-4- 8 azabicyclo[;3.2.2]-3-nonane in free base form, b.p. 73 -."-74.%5, C. at 13 mm, n,=1,475,3, which was converted. into its hydrochloride. as follows: saidfree base .-,was dissolved in 300 ml. of dry ether and the. solutiontreated with ethereal hydrogen chloride until the mixture ,was strongly.aci d The resultin g'white precipitate (20.8 g.; m.p. 1283C.) was collected,' wa;sh,d with dry ether, dried in vacuo ammo... recrystallizedfrom acetonitrile and a little-.=ether, and dried in vacuo at 50C. toyield 3,5-dirnethyl-2- oxa-4 azabicyclo[3.2.2]- 3-nonanc hydrochloride,m.p. 142C. When this hydrochloride-salt in aqueoussolution is heatedonfa steam bath by the procedure described above for conversion of thesolution of the corresponding bisulfate salt from the2-oxa-4-azabicyclo[3.2.21-3-nonane to the monocyclic4-aminocyclohexanol, there is obtained 4-amino-4-methylcyclohexanol.

, Following the procedures described in Example A-] or A-2 but usingmolar equivalent quantities of the appropriate reactants, the compoundsof Examples A-4 through A-7 are produced.

' 3. 4-Methyl-4-propionamidocyclohexanol using4-amino-4-methylcyclohexanol and propionic anhydride as in Example A-2.

4. 4-Acetamido-4-ethylcyclohexan ol using 4-amino-4-ethylcyclohexanoland acetic anhydride as in Example A-2.

5. 4-Propionamidocyclohexanol using 4- propionamidophenol as in ExampleA-l. l

6. 4-Butyramidocyclohexanol using 4' butyramidophenol as in Example A-l.

7. 4-Isobutyramidocyclohexanol using 4- isobutyramidophenol as inExample A-l.

B. 4-ACYLAM1NOCYCLOHEXANONES.

l. 4-Acetamidocyclohexanone To a stirred solution cooled to 10C. andcontaining 471 g. of 4- acetamidocyclohexanol, 3 liters of acetone and450 ml. of water was slowly added a solution containing 210 g. ofchromium trioxide in 900 ml. of water and 183 ml. of concentratedsulfuric acid, the addition being at such a rate as to keep the reactiontemperature at 7 about 15C. The reaction mixture was then stirred atroom temperature for several hours and then allowed "to stand at roomtemperature overnight'(about 15 hours). The liquid was decanted from thesemi-solid blue green salts and most of the solvent was removed atreduced pressure. The residue was combined with saturated salts; 300 ml.of water was added; and; the mixture was neutralized with so'lid sodiu'm carbonate. The mixture was shaken wellwith-s w'arm chloroform,

' filtered and the layers separated:-The chl0roform layer was heated invacuo to 'remove"thesolve nt and the remaining white solid wasrecrystallized from dry acetone to yield 284 g. of 4-acetamidocyc'lohexanone,m.p. 1331=36C. 1

Following theprocedure described in Example 8-1 but using a molarequivalent quantity of the appropriate4-(lower-alkanoylamide)-4-R-cyclohexanol, the

compounds of Examples -B-2 through B-6 are. produced. 2.4-Acetamido-4-methylcyclohexanone from""4=acetamido-4-methylcyclohexanol.

3. 4-Acetamido-4-ethylcyclohexanone from 4- acetamido4-ethy1cyclohexanol. t 4'. i 4-Propionamidocyclohexanon from 4-*propionamidocyclohexanol.

6; 4-Isobutyramidocyclohex'anone from 4- isobutyramidocyclohexanol.w-r vC. 9-ACYLAMlDO-3-NlTRO-l ,S-DIOXAS- PlRO[5.5]UNDECANES 1.N-(3-Methy1-3-nitro-l ,5-dioxaspiro[5.5 ]undecan- 9-yl)-acetamide Astirred mixture containing 9.3 g. of 4'acetamidocyclohexanone, 8.12 g.of 2-methyl-2- nitro-l,3-propanediol, 0.05 g. of p-toluenesulfonic acidmonohydrate and 150 ml. of benzene was boiled under reflux for twentyhours with a continuous separator connected to the reaction vessel tocollect the water formed by the reaction. The reaction mixture wasshaken well with 50 ml. of 5% aqueous sodium bicarbonate solution; thephases were separated and the aqueous phase was extracted withchloroform; the benzene phase and chloroform extract were combined anddried over anhydrous potassium carbonate; and, the

benzene and chloroform were distilled off in vacuo to leave 16.4 ofcrystalline solid which was recrystallized from chloroform-benzene anddried for 18 hours at 50C. and one-third atmosphere to yield 11.1 g. ofN (3-methyl-3-nitro-l ,5dioxaspiro[ 5 .5 ]undecan-9-yl acetamide, mp.158159C.

2. N-(3-Nitro-1,5-dioxaspiro[5.5]undecan-9-yl)-' acetamide-A mixture of26.4 g. of 4-acetamidocyclohexanone and 19.3 g. of2-nitro-l,3-propanediol was dissolved in 100 ml. of acetonitrile withslight warming. To this solution was added 22.7 g. of boron trifluorideetherate and the resulting solution was heated on a steam bath forfifteen minutes allowing the ether to distill off, whereupon thereaction temperature increased to about 80C. Most of the solvent wasdistilled off under reduced pressure and the residue was poured, withstirring, into a mixture containing 14g. of potassium carbonate in 220ml. of ice and water. The mixture was extracted with chloroform; thechloroform extract was dried over anhydrous potassium carbonate; and thechloroform was distilled off in vacuo to yield a very viscous oil whichcrystallized at room temperature. The crystalline product wasrecrystallized from 300 ml. of acetone to yield 12.81 g. of N-( 3-nitrol,5-dioxaspiro[5 .5 ]undecan-9- yl)acetamide, m.p. 170-172 C. A smallsample was recrystallized from methanol and was found to melt atl77178C.

3. N-(3-Ethyl-3-nitro-l ,5-dioxaspiro[5.5]undecan-9- yl)acetamide, 31.8g. as a clear, very viscous oil, was obtained following the proceduredescribed in Example C-l using 15.5 g. of 4-acetamidocyclohexanone, 16.4g. of 2-ethyl-2-nitro-l,3-propanediol, 0.5 g. of p-toluenesulfonic acidmonohydrate, and 150 ml. of benzene.

Following the procedure described in Example C-l but using molarequivalent quantities of the appropriate4-(lower-alkanoylamino)-4-R-cyclohexanone and2-nitro-2-R-l,3-propanediol, respectively, the compounds of Examples C-4through C-9 are produced.

4. N-(3-Methyl-3-nitro-1,5-dioxaspiro[5.5]undecan- 9-yl)propionamideusing 4-propionamidocyclohexanone and Z-methyl-Z-nitro- 1,3-propanediol.

5. N-(3-Methyl-3-nitro-1,5-dioxaspiro[5.5]undecan- 9-yl)butyramide using4-butyramidocyclohexanone and 2-methyl-2-nitro-l ,3-propanediol.

6. N-(3-Methyl-3-nitro-1,5-dioxaspiro[5.5]undecan- 9-yl)isobutyramide 7using 4- isobutyramidocyclohexanone and 2-methyl-2-nitro-1,3-propanediol. i

7. N-( 3,9-Dimethyl-3-nitro-l ,5-dioxaspiro[5.5 ]undecan-9-yl)acetamideusing 4-acetamido-4- methylcyclohexane and 2-rnethyl-2-nitro-l,3-

propanediol.

l 8. N-(3,9 Diethyl-3-nitro-1,5-dioxaspiro[5.5]undecan-9-yl)acetamideusing 4-acetamido-4-ethylcyclohexanone and2-ethyl-2-nitro-l,3-propandiol.

9. N-(9-Methyl-3-nitro-1,5-dioxaspiro[5.5]undecan- 9-yl)acetamide using4-acetamido-4-rnethylcyclohexanone and 2-nitro-l,3-propanediol.

D. 9-ACYLAMlDO-3-AMlNO-l ,5-D1OXAS- PlRO[5.5]UNDECANES l. N-(3-Amino-3-methyll ,5-dioxaspiro[ 5.5 ]unde-' can-9-yl)acetamide Amixture containing 200 g. of N-( 3-methy1-3-nitrol ,5-dioxaspiro[5.5]undecan-9- yl)acetamide, 10 g. of Raney nickel and sufficient 95%ethanol to produce a total volume of 17 ml. was treated under catalytichydrogenation conditions at 5060C. for 5 hours stirring with an initialhydrogen pressure of 950 psi and ending with the hydrogen pressure of650 psi. The reaction mixture was filtered and the filtrate heated on asteam bath in vacuo to remove the solvent. thereby yielding, as a clearviscous oil. 185 g. of N-( 3- amino-3-methyll ,5-dioxaspiro[ 5.5]undecan-9- yl)acetamide.

2. N-( 3-Amino-1 ,5-dioxaspiro[ 5.5 ]undecan-9- yl)acetamide, 12.1 g. asa viscous oil, was prepared following the procedure described in ExampleD-l using 12.8 g. of N-( 3-nitro-l ,5-dioxaspiro[5.5]undecan-9-yl)acetamide, 300 ml. of tetrahydrofuran as the solvent, l teaspoonfulof Raney nickel,.a'reaction temperature of 4050C. and initial hydrogenpressure of 980 psi and a final hydrogen pressure of 950,.psi.

3. N-( 3-Amino-3-ethyl-l ,5-dioxaspiro[ 5.5 ]undecan- 9-yl)acetamide,25.5 g. as a clear viscous oil; wasgprepared following the proceduredescribed in Example D-l using 28.6 g. of N-(3-ethyl-3-nitro-'l ,5-dioxaspiro[5.5]undecan9-yl)acetamide, 300 :ml. of 95% ethanol, 3teaspoonsful of Raney nickel, reaction temperature of 27C. and initialhydrogen pressure of 1,000 psi and a final hydrogen-pressure of 900 psi.

Following the procedure described in Example vD-l but using a molarequivalent quantity of the appropriateN-(3-R-3-nitro-9-R-l,5-dioxaspiro[5.5]undecan- 9-yl)alkanamide, thecompounds of Examples D-4 through D-9 are produced.

4. N-(3-Amino-3-methyll ,5- dioxaspiro[ 5.5 ]unde can-9-yl)propionamidefrom -N 3-methyl-3-nitro; 1, 5-dioxaspiro[5.5]undecan-9- yl)propionamide.-,

5. N-( 3-Amino-3-methyl-l ,5-dioxaspiro[5.5 ]undecan-9-yl)butyramidefrom N-(3-methyl-3-nitro-l,5- dioxaspiro[5.5 ]undecan-9-yl)butyramide.

6. N-( 3-Amino-3-methyl-l ,5'dioxaspiro[ 5.5 ]undecan-9-yl)isobutyramidefrom N-(3-methyl-3-nitro-l,5- dioxaspiro[S .5 undecan-9-yl)isobutyramide.

7. N-(3-Amino-3,9-dimethyl-1,5- dioxaspiro[5.5]undecan-9-yl)acetamidefrom N-(3,9- dimethyl-3-nitrol ,5-dioxaspiro[5 .5 ]undecan-9-yl)acetamide.

8. N-( 3-Amino3,9-diethyl-l ,5-dioxaspiro[5.5 ]undecan-9-yl)acetamidefrom N-(3,5-diethyl-3-nitro-1,5- dioxaspiro[ 5 5 ]undecan-9-yl)acetamide.

9. N-(3-Arnino-9-methyl-l,5-dioxaspiro[5.5]undecan-9-yl)acetamide fromN-(9-methyl-3-nitro-l,5- dioxaspiro[5.5]undecan-9-yl)acetamide.

E. 1,S-DIOXASPIRO[5.5]UNDECANE-3,9-

DIAMINES 1. 3-Methyl-l ,5-dioxaspiro[ 5.5 ]undecan-3,9-

ture was allowed to COOl to about 50C. and was then concentrated invacuo by heating on a steam bath until a semi-solid residue appeared. Tothe mixture was added two liters of ethyl acetate and the resulting warmmixture was stirred for residue appeared. To the mixture was added twoliters of ethyl acetate and the resulting warm mixture was stirred forseveral minutes, filtered and the filter-cake washed with warm ethylacetate. The layers of the filtrate were separated and the ethyl acetatelayer was dried over anhydrous potassium carbonate. The dried solutionwas concentrated in vacuo to remove the ethyl acetate thereby leaving,as a clear, amber oil, 300 g. of 3-methyl-l,5-dioxaspiro[5.5]undecan-3,9-diamine. A 240 g. portion of this diamine wasdissolved in isopropyl alcohol and to the solution was added a slightexcess of concentrated hydrochloric acid whereupon the dihydrochloridesalt separated. After the mixture had been cooled, the precipitate wascollected and washed successively with dry ether and absolute ethanol toyield 152 g. of 3-methyl- 1 ,5-dioxaspiro[5.5 ]undecan-3,9-diaminedihydrochloride, m.p. 258260C.

2. 1,5Dioxaspiro[5.5]undecan-3,9-diamine, 5.6 g. as a clear, colorless,viscous oil, b.p. 108-120C. at 0.02 mm., was prepared following theprocedure described in Example E-l using 12.0 g. of N-(3-amino-l,5-dioxaspiro[5.5]undecan-9-yl)acetamide, a solution of 8.0 g. of potassiumhydroxide in 50 ml. of water, a reflux period of 3 hours, chloroform asthe extracting solvent and fractional distillation under reducedpressure of the oil remaining after removal of the chloroform.

3. 3-Ethyl-l,5-dioxaspiro[5.5]undecan-3,9-diamine, 8.25 g. as a clear,colorless, viscous oil, b.p. 1 1 13C. at 0.05 mm., was obtained as inExample E-l using 20.6 g. of N-(3-amino-3-ethyl-l,5-dioxaspiro[5.5]undecan-9-yl)acetamide. 10 g. of potassium hydroxide in100 ml. of water, a refluxing period of 5 /2 hours, ethyl acetate as theextracting solvent and purification of the product by fractionaldistillation under reduced pressure.

Following the procedure described in Example E-l but using in place ofN-(3-amino-3-methyl-l ,5- dioxaspiro[5.5]undecan-9-yl)acetamide a molarequivalent quantity of the appropriate N-( 3-amino-3-R-9-R'-1,5-dioxaspiro[5 .5]undecan-9-yl)alkanamide, the compounds of ExamplesE-4 through E-9 are produced.

4. 3-Methyll ,5-dioxaspiro[5.5 ]undecan-3,9- diamine from N-(3-amino-3-methyl-l ,5- dioxaspiro[5.5]undecan-9-yl)propionamide.

5. 3-Methyl-l ,5-dioxaspiro[ 5 .5 undecan-3 ,9- diamine fromN-(3-amino-3-methyl-1,5- dioxaspiro[5.5 ]undecan-9-yl )butyramide.

6. 3-Methyl-1,5-dioxaspiro[5.5]undecan-3,9- diamine from N-(3-amino-3-methyl-l ,5- dioxaspiro[5.5]undecan-9-yl)isobutyramide.

7. 3,9-Dimethyl-l,5-dioxaspiro[5.5 undecan-3,9- diamine from N-(3-amino-3,9-dimethyl-l ,5- dioxaspiro[ 5 .5 ]undecan-9-yl)acetamide.

8. 3 ,9-Diethyl-1,5-dioxaspiro[5.5]undecan-3,9- diamine from N-(3-amino-3,9-diethyl-l ,5- dioxaspiro[5.5]undecan-9-yl)acetamide.

9. 9-Methyl-l ,5-dioxaspiro[5.5 ]undecan-3,9- diamine fromN-(3-amino-9-methyl-1,S- dioxaspiro[5.5]undecan-9-yl)acetamide.

F. 3,9-Dl-(ACYLAM1DO)- 1,5-D1OXASP1RO[5.- 5]UNDECANES 1. N,N-( 3-Methyll,5-dioxaspiro[5.5 ]undecan- 3,9diyl)bis(4-trifluoromethoxybenzamide) Toa stirred mixture containing 8.0 g. of 3-methyl-1,5-dioxaspiro[5.5]undecan-3,9-diamine in 50 ml. of dry ethylene dichloride,50 ml. of 10% aqueous potassium carbonate solution and 25 ml. of water,chilled to 10C. in an ice bath was added dropwise with stirring over aperiod of 1 hour a solution containing 19.3 g. of4-trifluoromethoxybenzoyl chloride in 50 ml. of dry ethylene dichloride.The mixture was stirred while warming to room temperature and then foran additional 2 hours at room temperature. After the mixture had beenstirred overnight at 5C.. it was shaken well with 100 ml. of chloroformand the layers separated. The chloroform layer was dried over anhydrouspotassium carbonate and the chloroform distilled off under reducedpressure. The remaining white solid was recrystallized from ethylenedichloride-n-hexane to yield 15.14 g. of N,N- (3-methyl-l,5-dioxaspiro[5.5 ]undecan-3 .9-diyl)bis( 4- trifluoromethoxybenzamide,m.p. 202.5203.5C. Evaporation of the mother layer to drynessunderreduced pressure gave 7.4 g. of white solid which wasrecrystallized, using decolorizing charcoal, from ethylenedichloride-n-hexane to yield another 6.3 g. of the product, m.p.20l203C.

2. N,N'-(3-Methyl-l,5-dioxaspiro[5.5]u ndecan-3,9- diyl )bis(4-methoxybenzamide 6.1 g., m.p. 203204C., was prepared following theprocedure described in Example F-l using 4.46 g. of 3-methyl-1,5-dioxaspiro[5.5]undecan-3,9-diamine in 50 ml. of ethylene dichloride, 7.0g. of potassium carbonate in ml. of water, 8.55 g. of 4-methoxybenzoy1chloride in 50 ml. of ethylene dichloride, and recrystallization fromabsolute ethanol using decolorizing charcoal.

3. N,N-(3-Methy1-l,5-dioxaspiro[5.5]undecan-3,9-diyl)bis(4-difluoromethoxybenzamide), 21.1 g., m.p. 200-201C., wasprepared following the procedure described in Example F-l using 13.6 g.of 3-methyl-1,5- dioxaspiro[5.5]undecan-3,9-diamine dihydrochloride in100 ml. of water, 27.6 g. of potassium carbonate in 100 ml. of ethylenedichloride and 20.7 g. of 4- difluoromethoxybenzoyl chloride in 50 ml.of ethylene dichloride; isolating the solid product from the reactionmixture by filtration; and, recrystallizing it from isopropyl alcohol.

4. N,N'-(3-Ethyl-l,5-dioxaspiro[5.5]undecan-3,9-diyl)bis(4-trifluoromethoxybenzamide), 18.9 g.,,m.p. 184-185.5C., wasprepared following the procedure described in Example F-l using 8.25 g.of 3-ethyl-l,5- dioxaspiro[5.5]undecan-3,9-diamine in 100 ml. ofethylene dichloride, 13.8 g. of potassium carbonate in m1. of water,17.2 g. of 4-trifluoromethoxybenzoyl chloride in 40 ml. of ethylenedichloride, and recrystallization from chloroform.

5. N,N'-( l ,5Dioxaspiro[5.5 ]undecan-3,9-diyl)bis-(4-trifluoromethoxybenzamide), 1 1.4 g., m.p. 260-26lC., was preparedfollowing the procedure described in Example F-l using 5.6 g. of 1,5-dioxaspiro[5.5]undecan-3,9-diamine in 50 ml. of ethylene dichloride, 8.3g. of potassium carbonate in ml. of water, 13.5 g. of4-trifiuoromethoxybenzoyl chloride in 50 ml. of ethylene dichloride, andrecrystallization from carbon tetrachloride-methanol.

6. N-(9-Acetamido-3-methyl-1,5- dioxaspiro 5 .5 ]undecan-3-yl)-4-trifluor omethoxybenzamide, 8.26 g., m.p. l97-l98C., was preparedfollowing the procedure described in Example F-l using 7.8 ,g. ofN-(3-amino-3-methyl-l,5- dioxaspiro[5.5]undecan-9-yl)acetamide in 50 ml.of ethylene dichloride, 5.5 g. of potassium carbonate in 60 ml. ofwater, 8.3 g. of 4-trifluoromethoxybenzoyl fluoride in 50 ml. ofethylene dichloride, and recrystallization from carbontetrachloride-methanol.

7. N,N-(3,9-Diemethyl-l,5-dioxaspiro[5.5]undecan-3,9-diyl)bis(4-trifluoromethoxybenzamide), 5.4 g., amorphous whitepowder, was prepared following the procedure described in Example F-lusing 4.5 g. of 3 ,9-dimethyll ,5-dioxaspiro[5.5]undecan-3 ,9-diamine in50 ml. of ethylene dichloride, 2.1 g. of potassium carbonate in 50 ml.of water, and 2.5 g. of 4-trifluoromethoxybenzoyl chloride in ml. ofethylene dichloride.

8. N-(9-Acetamido-3-ethyl-l ,5- dioxaspiro 5.5 ]undecan-3-yl)-4-trifluoromethoxybenzamide, 5.7 g., m.p. 198-l99C., was preparedfollowing the procedure described in Example F-l using 5.0 g. ofN-(3-amino-3-ethyl-l,5-dioxaspiro[5.5]undecan- 9-yl)acetamide in 50 ml.of ethylene dichloride, 2.76 g. of potassium carbonate in 80 ml. ofwater, 4.38 g. of 4-trifluoromethoxybenzoyl chloride in 50 ml. ofethylene dichloride, and recrystallization twice fromchloroform-n-hexane.

9. N-(9-Acetamido-3-methyl-1,5-dioxaspiro[5.5]undecan-3-yl)-4-methoxybenzamide, 31.2 g., m.p. 227-228C.(sint. 225C), was prepared following the procedure described in ExampleF-l using 24.23 g. of N-(3-amino-3-methyl-l,5-dioxaspiro[5.5]undecan-9-yl)acetamide in 125 ml. of ethylene dichloride,26.54 g. of potassium carbonate in 125 ml. of water, 14.9 ml. of4-methoxybenzoyl chloride in 75 ml. of ethylene dichloride, andrecrystallization from acetonitrile.

10. N,N'-(3-Methyl-l,5-dioxaspiro[5.5]undecan-3,9-diyl)bis(a.a-dichloroacetamide), 13.2 g., m.p. 208209C., wasprepared following the procedure described in Example F-l using 8.0 g.of 3-methyl-1,5- dioxaspiro[5.5 ]undecan-3,9-diamine in 70 ml. ofethylene dichloride, 15.2 g. of potassium carbonate in 100 ml. of water,14.7 g. of a,a-dichloroacetyl chloride in 50 ml. of ethylene dichloride,and recrystallization from methanol.

1 l. N,N'-(3-Methyl-l,5-dioxaspir0[5.5]undecan-3,9-diyl)bis(a,a,a-trifluoroacetamide) To a stirred, cooled (ice bath)solution of triethylamine in 200 ml. of tetrahydrofuran was addeddropwise over a period of twenty minutes 27.4 g. of trifiuoroaceticanhydride. To this stirred solution at 4C. was added dropwise withcontinued cooling a solution of 13.0 g. of 3-methyl-l ,5-dioxaspiro[5.5]undecan-3,9-diamine in an equal volume (13 ml.) of drytetrahydrofuran, keeping the reaction mixture below 10C. The solutionwas stirred below 10C. for 1 hour, at room temperature for an additionalthree hours and then poured into a mixture of 1200 m1. of ice and water.The precipitate was collected and recrystallized from 95% ethanol toyield 14.4 g. of N,N-(3-methyl-l,5-dioxaspiro[5.5]undecan-3,9-diyl)bis(a,a,atrifluoroacetamide), m.p. 233234.5C.

Following the procedure described in Example F-l but using molarequivalent quantities of the appropriate3-R-9-R-1,5-dioxaspiro[5.5]undecan-3,9-diamine and 4-Q,-benzoyl halide,the compounds of Examples F-12 through F-19 are obtained.

6 12. N,N-(3,9-Diethyl-l,5-dioxaspiro[5.5]undecan- 53,9-diyl)bis(4-trifluoromethoxybenzamide) using 3,9- diethyl- 1,5-dioxaspiro[5 .5 ]undecan-3,9-diamine and 4-trifluoromethoxybenzoylchloride.

13. N,N-(3-Methyl-l ,5-dioxaspiro[5.5]undecan-3,9-diyl)bis(4-trichloromethoxybenzamide) using 3-methyl-l,5-dioxaspiro[5.5]undecan-3,9-diamine and4-trichloromethoxybenzoyl chloride.

14. N,N-(3-Methyl-l ,5-dioxaspiro[5.5 ]undecan-3,9-diy1)bis[4-(2,2,2-trif1uoroethoxy)benzamide] using 3-methyl- 1,5-dioxaspiro[5.5 ]undecan-3.9- diamine and4-(2,2,2-trifluoroethyxy)benzoyl chloride.

15. N,N'-(3-Methyl-l ,5-dioxaspiro[ 5.5]undecan-3,9-diyl)bis[4-(2-chloro-1,l,2-trifluoroethoxy)benzamide] using3-methy1-l ,5-dioxaspiro[5.5]undecan-3,9- diamine and4-(2-chloro-l,1,2-trifluoroethoxy)benzoyl chloride.

16. N,N'-(9Methyl-l ,5-dioxaspiro[ 5.5 ]undecan-3,9-diyl)bis(4-trifluoromethoxybenzamide) using 9-methyl-l,5-dioxaspiro[5.5]undecan-3,9-diamine and4-trifluoromethoxybenzoyl chloride.

17. N,N'-(3-Methyl-l,5-dioxaspiro[5.5]undecan-3,9-diyl)bis[4-(2,2,3,3,3-pentafluoroethoxybenzamide)] using3-methy1-l,5-dioxaspiro[5.5]undecan- 3,9-diamine and4-(2,2,3,3,3-pentafluoroethoxy)benzoyl chloride.

l8. N,N'-(3-Methyl-l,5-dioxaspiro[5.5]undecan-3,9-diyl)bis(4-ethoxybenzamide) using 3-methyl-l,5-dioxaspiro[5.5]undecan-3,9-diamine and 4- ethoxybenzoyl chloride. v

19. N,N-( 3-Methyl-l ,5-dioxaspiro[5.5 ]undecan-3,9-diyl)bis(4-isopropoxybenzamide) using 3-methyl- 1,5-dioxaspiro[5.5]undecan-3,9-diamine and 4- isopropoxybenzoyl chloride.

Following the procedure described in Example F-6 but using molarequivalent quantities of the appropriate 3-amino-3-R-9-R'-l,5-dioxaspiro[5.5 ]undecan-9- yl)acylamide and 4-Q -benzoyl halide, thecompounds of Examples F-2O through F-25 are obtained.

20. N-( 3-Methyl-9-propionamidol ,5- dioxaspiro[ 5.5]undecan-3-yl)-4-trifluoromethoxybenzamide using N-( 3-amino-3-methyl-l,5- dioxaspiro[5.5]undecan-9-yl)propionamide and4-trifluoromethoxybenzoyl chloride.

21. N-(9-Butyramido-3-methy1-1,5- dioxaspiro 5.5 ]undecan-3-yl)-4-trifluoromethoxybenzamide using N-( 3-amino-3-methyl-l ,5-dioxaspiro[5.5]undecan-9-yl)butyramide and 4-trifluoromethoxybenzoylchloride.

22. N-(9-lsobutyramido-3-methyl-1,5-dioxaspiro[5.5]undecan-3-yl)-4-trifluoromethoxybenzamide usingN-(3-amino-3-methyl-1 ,5- dioxaspiro[5.5]undecan-9-yl)isobutyramide and4-trifluoromethoxybenzoyl chloride.

23. N-(9-Acetamido-3,9-dimethyl-1,5- dioxaspiro[ 5.5 ]undecan-3-yl)-4-trifluoromethoxybenzamide using N-( 3-amino-3 ,9-dimethyll ,5-dioxaspiro[5.5]undecan-9-yl)acetamide and 4-trifluoromethoxybenzylchloride.

24. N-(9-Acetamido-3,9-diethyll ,5- dioxaspiro[5.5]undecan-3-y1)-4-trifluoromethoxybenzamide using N-(3-amino-3,9-diethyl-l ,5- dioxaspiro[5.5]undecan-9-yl)acetamide and4-trifluoromethoxybenzoyl chloride.

25. N-(9-Acetamido-9-methyl-1,5- dioxaspirol 5 .5 ]undecan-3-yl)-4-trifluoromethoxybenzamide using N-(3-amino-9-methyll ,5-dioxaspiro[5.5 ]undecan-9-y1)acetamide 4-trifluorormethoxybenzoylchloride.

The antifertility activity of the compounds of formula 11 was determinedby the following standard test proceand dure which involves female ratswhich are medicated prior to, during and after the mating period. Therats are autopsied on the fourteenth post mating day and the uteri areexamined for evidence of pregnancy. The procedural details are asfollows: A colony of sexually mature female rats of the Sprague-Dawleystrain weighing 200-300 gms. are maintained on routine laboratory care.Daily vaginal smears are examined to recored the cyclic characteristicsof each rat. A given test is composed of rats which have exhibited aminimum of three coincidental estrus cycles. Three days prior to anexpected estrus the rats to be placed on test are grouped, housedindividually and placed on medication. The medication consists of a testcompound, prepared as a solution or suspension in a suitable vehicle,administered orally via stomach tube once daily for a total of eightmedications in a 10 day period (Sunday medications are omitted). Onegroup receives only the vehicle in a like manner to serve as a control.Late in the afternoon of the day preceding the expected estrus a matureproven fertile male is housed with each female overnight. The followingmorning all males are removed and a vaginal smear of each female isexamined for the presence of spermatoza as evidence that inseminationhas occurred. Medication of all inseminated rats is continued throughthe seventh post insemination day. The rats are autopsied seven daysafter the last medication and the uteri removed and examined forevidence of pregnancy. The number of implantation sites, number ofresorption sites, total number of fetuses and the number of viablefetuses are recorded. When tested by this procedure, the compounds offormula II were found to have antifertility activity at dose levelsranging from about to 400 mg. per kg. per day. Illustrative compounds offormula I] found to have antifertility activity as determined by theabove procedure include: N,N 3-methyll ,5-dioxaspiro[5.5 ]undecan-3,9-diyl)bis(4-trifluoromethoxybenzamide), N,N-(3- methyl-l,5-dioxaspiro[5.5]undecan-3,9-diyl )bis(4- methoxybenzamide), N,N3-ethyl-1 ,5-dioxaspiro[5.5]undecan-3,9-diyl)bis(4-trifluoromethoxybenzamide N-(9-acetamido-3-methyll ,5- dioxaspiro[ 5 .5 ]undecan-3-yl)-4-trifluoromethoxybenzamide and N-( 9-acetamido-3-ethyl-l ,5-dioxaspiro[5.5]undecan-3-yl)-4-trifluoromethoxybenzamide.

The actual determination of the numerical antifertility data definitivefor a particular compound is readily 16 obtained by standard testprocedures, referred to above, by technicians versed in endocrinologicaltest procedures, without any need for any extensive experimentation.

The compounds of formula II can be prepared for use by conventionalpharmaceutical procedures: that is, by dissolving or suspending them ina pharmaceutically acceptably vehicle, e.g., aqueous alcohol, glycol,oil solution, or oil-water emulsion, for parenteral or oraladministration; or by incorporating them in unit dosage form as tabletsor capsules for oral administration either alone or in combination withconventional adjuvants, e.g., calcium carbonate, starch, lactose, talc,magnesium stearate, gum acacia, and the like.

We claim:

1. A compound of the formula Ac NH wherein R and R are each hydrogen orlower-alkyl;

Ac is hydrogen, lower-alkanoyl or polyhalo-acetyl only when Q is NHAcand, Q is N0 NH or NHACZ where Ac is polyhaloacetyl.

2. A compound according to claim 1 where R is hydrogen and R islower-alkyl.

3. A compound according to claim 2 where Ac is lower-alkanoyl and Q isN0 4. A compound according to claim 2 where Ac, is lower-alkanoyl and Qis NH 5. A compound according to claim 2 where Ac is hydrogen and Q isNH 6. N-( 3-methyl-3-nitro-l ,5-dioxaspiro[5 .5 ]undecan- 9-yl)acetamideaccording to claim 3.

7. N-(3-amino-3-methyl-l ,5-dioxaspiro[5.5 ]undecan-9-yl)acetamideaccording to claim 4.

8. 3-Methyl-l ,5-dioxaspiro[5.5]undecan-3,9- diamine according to claim5.

9. N,N'-(3-methyl-l,5-dioxaspiro[5.5]undecan-3,9-diyl)bis(a,a-dichloroacetamide) according to claim 2.

10. N,N'-(3-methyl-l ,5-dioxaspiro[5.5]undecan-3,9-

yl)bis( a,a,a-trifluoroacetamide) according to claim 2.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. I3,895,036

DATED July 15, 1975 INVENT R( 1 Karl O. Gelotte and Alexander R. Surreylt is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 1, line 2, "[5,5]" should read Column 1, line 4, omit"COMPOSITIONS AND THEIR PREPARATION" Column 5, line 48,"loweralkanoylating" should read lower-alkanoylating Column 6, line 36,"19-" should read Signed and Scaled this twenty-first D21) Of October1975 [SEAL] Attest:

RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner uj'Parenrsand Trademarks

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 whereR'' is hydrogen and R is lower-alkyl.
 3. A compound according to claim 2where Ac1 is lower-alkanoyl and Q is NO2.
 4. A compound according toclaim 2 where Ac1 is lower-alkanoyl and Q is NH2.
 5. A compoundaccording to claim 2 where Ac1 is hydrogen and Q is NH2. 6.N-(3-methyl-3-nitro-1,5-dioxaspiro(5.5)undecan-9-yl)acetamide accordingto claim
 3. 7.N-(3-amino-3-methyl-1,5-dioxaspiro(5.5)undecan-9-yl)acetamide accordingto claim
 4. 8. 3-Methyl-1,5-dioxaspiro(5.5)undecan-3,9-diamine accordingto claim
 5. 9. N,N''-(3-methyl-1,5-dioxaspiro(5.5)undecan-3,9-diyl)bis(Alpha , Alpha -dichloroacetamide) according to claim
 2. 10.N,N''-(3-methyl-1,5-dioxaspiro(5.5)undecan-3,9-yl)bis( Alpha , Alpha ,Alpha -trifluoroacetamide) according to claim 2.